The acquisition of resistance to multiple drugs by tumor cells is a critical problem in cancer therapy. Various multidrug resistant cell lines have been identified and include, for example, rodent cell lines resistant to multiple drugs as well as multidrug resistant (MDR) lines derived from the human KB carcinoma cell line (a HeLa subclone) selected for resistance to either colchicine, vinblastine, or adriamycin which have been extensively studied (see, e.g., Kartner et al. Science 221:1285-1288 (1983), Akiyama et al. Somatic Cell Mol. Genet. 11: 117-126 (1985); and Shen et al. J. Bio. Chem. 261: 7762-7770 (1986)).
It has been reported that two human DNA sequences designated MDR1 and MDR2, which are homologous to the previously isolated hamster mdr gene (Roninson et al. Nature, 309: 626-628 (1984); Gros et al. Proc. Natl. Acad. Sci. USA, 83: 337-341 (1986)) are amplified in MDR human KB carcinoma cell lines (Fojo et al. Proc. Natl. Acad. Sci. USA 82: 7661-7665 (1985); Roninson et al. Proc. Natl. Sci. USA 83: 4538-4542 (1986)). The MDR1 gene encodes a 4.5-kb mRNA which is overexpressed in all of the highly drug-resistant sublines (Roninson et al. supra; Shen et al. Science, 232: 643-645 (1986)) and in certain normal and tumor tissues (Fojo et al. Proc. Natl. Acad. Sci. USA 84: 265-269 (1987)).
The human MDR1 gene is amplified and expressed in mouse cells transformed to multidrug resistance by genomic DNA from MDR human cells, suggesting that expression of the MDR1 gene is responsible for development of the MDR phenotypes (Shen et al. Mol. Cell. Biol. 6: 4039-4044 (1986)). Recent data demonstrates that the cloned mouse mdr gene is sufficient to confer multidrug resistance when introduced into cells in an expression vector (Gros et al. Nature, 323: 728-731 (1986). Ueda et al. J. Biol. Chem., 262: 505-508 (1987) and Chen et al. Cell 47: 381-389 (1986) have described the isolation of a set of overlapping cDNAs for the entire coding region of the human MDR1 mRNA. However, the construction of a full-length cDNA containing the entire coding region of the human multidrug resistance gene (MDR1) the incorporation of such an MDR1 cDNA into a vector, and the use of such a vector to achieve efficient expression of the cloned gene to confer multidrug resistance in transfected drug-susceptible recipient cells, has not heretofore been disclosed or accomplished.